Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells

Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13182-7. doi: 10.1073/pnas.95.22.13182.

Abstract

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / pharmacology
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Cell Membrane / drug effects
  • Cell Membrane / pathology
  • Cell Membrane / ultrastructure
  • Dietary Fats
  • Drug Combinations
  • Drugs, Chinese Herbal / toxicity
  • Flavanones*
  • Flavonoids / toxicity
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Hydroxyeicosatetraenoic Acids / pharmacology
  • Ibuprofen / toxicity
  • Indoles / toxicity
  • Leukotriene B4 / pharmacology
  • Lipoxygenase Inhibitors* / toxicity*
  • Male
  • Mitochondria / pathology
  • Mitochondria / physiology
  • Mitochondria / ultrastructure
  • Models, Biological
  • Nucleosomes / drug effects
  • Nucleosomes / pathology
  • Oxidative Stress
  • Permeability
  • Phosphatidylserines / metabolism
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology*
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Dietary Fats
  • Drug Combinations
  • Drugs, Chinese Herbal
  • Flavanones
  • Flavonoids
  • Hydroxyeicosatetraenoic Acids
  • Indoles
  • Lipoxygenase Inhibitors
  • Nucleosomes
  • Phosphatidylserines
  • shakuyaku-kanzoh-toh
  • MK-886
  • Leukotriene B4
  • 5-hydroxy-6,8,11,14-eicosatetraenoic acid
  • baicalein
  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Ibuprofen